There are many forms of squamous cell carcinoma (SCC) in humans for which existing therapeutic modalities are inadequate. There are also very few useful animal models of SCC in which new therapies could be evaluated. This laboratory has previously developed a transgenic model in which susceptibility to benign skin papillomas is greatly increased. This model, the K6/ODC (B6) transgenic mouse, overexpresses an omithine decarboxylase transgene (ODC) in skin and other epithelial tissues. When placed on a FVB genetic background, carcinogen-exposed K6/ODC (FVB) mice developed SCCs rapidly and in high multiplicity. Further, treatment of SCC-bearing mice with the ODC inhibitor adifluoromethylornithine (DFMO) caused rapid tumor regression and apparent cures. Thus, for the first time, a useful preclinical model of SCC is available for research into the genetics and treatment of this disease. To further explore the potential of polyamine-based (i.e. DFMO) therapy for SCC, the following specific aims will be addressed: (1) Further characterization of the response of K6/ODC (FVB) mice to polyamine-based therapy, including a dose/response study of DFMO and studying the combination of DFMO with one or more polyamine uptake inhibitors. (2) Mechanistic studies of polyamine-dependent SCC regression, including measuring indices of cell proliferation, apoptosis, squamous differentiation, tumor angiogenesis, and global patterns of gene expression. (3) Genetics of susceptibility to SCC. The chromosomal location of FVB genes that predispose to SCC will be mapped in a large intercross involving K6/ODC mice on a C57BL/6J background (low SCC strain) and FVB (high SCC strain). The K6/ODC (FVB) model represents a unique opportunity to investigate new therapeutic modalities such as polyamine-based chemotherapy and to use mouse genetics to identify genes important in SCC development. Identifying those genes that are critical for murine SCC development could lead to the development of new approaches to the management of human SCC.